This is the final resubmission of a project designed to investigate differences between schizophrenic individuals and healthy volunteers in the effects of marijuana on the brain and behavior. The overall aim is to determine whether schizophrenia confers an increased liability to the cognitive and clinical effects of cannabis use. There is epidemiological evidence linking marijuana use with a higher incidence of schizophrenia. There is also evidence that acute psychosis can be induced by heavy marijuana use, as well as evidence that prolonged marijuana use can lead to the onset of schizophrenia in susceptible individuals. Additionally, injection of THC has been found to cause increased schizophrenia-like symptoms in healthy volunteers and to increase symptoms in patients with schizophrenia. Our research team has extensive expertise in assessing differences between schizophrenics and normal volunteers using cognitive and clinical indices, as well as sophisticated measures of brain structure and function. We are also experienced in assessing the effects of acute marijuana use on regional cerebral blood flow (rCBF) and cognition in non-schizophrenic users of marijuana. This R21 application proposes a study that links these two research programs. We propose acquiring PET and MR imaging data and clinical symptom ratings on 10 schizophrenic subjects and 10 matched normal volunteers who are regular users of marijuana. PET imaging with [15O]water will be used to measure rCBF data during a monetary reward protocol. Subjects will be scanned using PET with [15O]water on one occasion, before and after smoking a placebo cigarette, and before and after smoking an active marijuana cigarette. During PET imaging the subjects will perform a monetary reward task that was found to activate reward-related brain regions in other studies. The PET images will be co-registered to a high resolution structural MRI scan for analysis. The subjects will also be assessed on a separate occasion with a neuropsychological battery. The schizophrenic subjects will be matched by age, gender, parental SES, and smoking history to the normal volunteer subjects. We hypothesize that the effects of smoking marijuana on rCBF in schizophrenics will differ significantly from that seen in our normal volunteers. More specifically, we hypothesize that rCBF will be lower in brain reward systems in schizophrenic subjects at baseline (i.e., after smoking placebo), but will show a normal pattern of activation to reward after smoking marijuana. PUBLIC HEALTH RELEVANCE: There is increasing evidence that there is a link between marijuana use and schizophrenia, as well as evidence that schizophrenic individuals may have abnormalities in their brain reward systems. This study will use PET imaging during a reward task to compare blood flow changes in the brains of schizophrenics and healthy volunteers who regularly use marijuana after they smoke either a placebo or an active marijuana cigarette. Results of the study will further our understanding of the underlying causes of schizophrenia and could suggest new possibilities for treatment of this disorder.